Chrysanthemic acid preparation

ABSTRACT

Syntheses of chrysanthemic acid and esters involving reduction of 3,3,6,6-tetramethylbicyclo (3.1.0) hexane-2,4-dione, esterification to a sulfonic acid ester, and ring cleavage.

Unitefl States Patent 1 sim an [451 Apr. 17, 1973 CHRYSANTHEMIC ACID PREPARATION [52] US. Cl. ..260/456 R, 260/468 P, 260/514 B,

260/586 R, 260/617 F [51] Int. Cl ..'...C07c 143/68 [58] Field of Search ..'...260/456 R, 456 P [56] References Cited OTHER PUBLICATIONS Chemical Abstracts, Vol. 57, 13639i. Tetrahedron Letters, No. 5l, pp. 5,193-5,196 (1967), W. Reusch et al.

Primary ExaminerLeon Zitver Assistant ExaminerLeo B. De Crescente Attorney-Dona1d W. Erickson ABSTRACT Syntheses of chrysanthemic acid and esters involving reduction of 3,3,6,6-tetramethylbicyclo [3.1.0] hexane-2,4-dione, esterification to a sulfonic acid ester, and ring cleavage.

3 Claims, No Drawings CHRYSANTIIEMIC ACID PREPARATION to the unavailability and expense of starting materials and low yields. The syntheses of the present invention overcomes these disadvantages of the prior art.

One embodiment of the present invention is outlined asfollows; r

. 9 OH O: Od-R A (II) (In) O 0 1 ll C-OR1 0 OH (1 (v) R is methyl or tolyl and R is lower alkyl of one to six carbon atoms. In the practice of the above process, 2- hydroxy-3,3,6,6-tetramethylbicyclo [3. 1.0] hexan-4- one is converted into the corresponding mesylate or tosylate III using methanesulfonylchloride or ptoluenesulfonyl chloride in triethylamine or pyridine. A compound of formula III is reacted with alkali metal alkoxide (the alkoxy containing one to six carbon atoms) such as sodium methoxide, sodium ethoxide, potassium methoxide and potassium ethoxide to yield the lower alkyl chrysanthemate IV which is hydrolyzed to the chrysanthemic acid V. The preparation of the chrysanthemate IV is carried out in an organic solvent such as dimethylsulfoxide or tetrahydrofuran at a temperature of from about 25 to 75 C. The reaction is usually complete in from about 6 to 30 hours. By reacting the mesylate or tosylate III with strong base in aqueous organic solvent, chrysanthemic acid (V) is obtained directly. This reaction can be carried out using,

for example, sodium hydroxide or potassium hydroxide in the presence of water in an organic solvent such as .dioxane, diglyme, monoglyme, tetrahydrofuran, and

the like. The reaction is generally carried out at above room temperature to the reflux temperature of thereaction mixture and is complete within minutes to several hours.

Another embodiment of the present invention is outlined as follows:

(VIII) In the practice of the above process, the diol VI is converted into the 4-mesylate or 4-tosylate VII using methanesulfonyl chloride or p-toluenesulfonyl chloride in triethylamine or pyridine. The compound of formula VII is then reacted with alkali metal hydride such as sodium hydride or potassium hydride or an alkali metal alkoxide such as potassium t-butoxide in an organic sol-1 vent such as tetrahydrofuran, dioxane, diglyme, and the like to yield the aldehyde VIII. The reaction is generally done at about room temperature, although tempera tures below and above room temperature can be used and is complete within minutes to a few hours. The aldehyde is then oxidized using manganese dioxide or othermild conditions to afford chrysanthemic acid V.

The starting materials 11 and VI are readily preparedf using the procedure outlined below.

(X) (XI) The diketone X is prepared from dimedone methyliodide and potassium carbonate in acetone and refluxing for several hours. Bromination of is plished using bromine in glacial acetic acid at room temperature for a few minutes. The bromide X1 is converted into the bicyclic diketone I using alkali metal hydride such as sodium hydride in tetrahydrofuran or the like. The reaction is complete within minutes to a few hours. Alternatively, the bicyclic diketone I can be prepared by treatment of the bromide XI with alkali metal alkoxide in dimethylformamide. Reduction of the diketone using sodium borohydride or lithium tri-tbutoxy aluminum hydride affords the mono-alcohol II. The diol V1 is prepared from the diketone I using lithium aluminum hydride.

The following examples are provided to illustrate the. practice of the present invention. Temperature is given in degrees Centigrade. 1

EXAMPLE 1 EXAMPLEZ To a cold (0) solution of 1.4 g. of 2-hydroxy-3,3,6,6- tetramethylbicyclo [3.1.0] hexan-4-one and 1.3 g. of; triethylarnine in 50 ml. of dichloromethane is addedl 1.04 g. of methanesulfonyl chloride over a period of 5; minutes. The solution is warmed to 25 and stirred for 2; hours. The mixture is poured into brine, diluted with:

ml. of ether, washed with saturated potassium;

bicarbonate and brine. The organic phase is dried over of dimethylsulfoxide and 15 ml. MeOl-l is added to a solution of 10 g. of 2-mesyloxy-3,3,6,6-tetramethylbicyclo [3.1.0] hexan4-one in 40 ml. of anhydrous di methylsulfoxide. The solution is heated at 50 for 18 hours, poured into 200 ml. of water, and extracted n'esium sulfate. The solvent is removed under reduced pressure, yielding cis-methyl chrysanthemate.

EXAMPLE 4 A solution of 10 g. of 2-mesyloxy-3,3,6,6- tetramethylbicyclo [3.1.0] hexan-4-one in 100 ml. of 30' percent aqueous dioxane is treated with a solution of 2.0 g. of sodium hydroxide in 50 ml. of water. The solution isrefluxed overnight. After cooling to 25, the

' solution is washed twice with ether. The aqueous phase is then acidified with dilute HCl and extracted several times with ether. The combined extracts are washed brine, 'dried over magnesium sulfate, and

' evaporated .under reduced pressure to yield cischrysanthemic acid as a crystallize solid which is pulifted by recrystallization. v

' The product obtained in examples 3 and 4 (predominately cis ester and acid, respectively), can be epimerized by known procedures to the trans isomer.

' See, for example, US. Pat. Nos. 3,046,299 and 3,538,143 and l-lanafusa, Chem. and Ind., 1050 1970).

EXAMPLE 5 A solution of g. of 3,3,6,6-tetrarnethylbicyclo [3.1.0] hexa-2,4dione in 50 ml. of ether is added dropwise to a solution of 2 g. of lithium aluminum hydride in 50ml. of ether. After stirring for 14 hours at 25 under an inertatmosphere, the'mixture is cooled in an ice bath and excess reagent hydrolyzed by the slow addition of 2 ml. of water, followed by 2 ml. of 15 percent aqueous sodium hydroxide solution, and 6 ml. of water. The granular precipitates are filtered. The ethereal filtrate is washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo to yield 2,4-dihydroxy-3,3,6,6-tetramethylbicyclo [3.1.0] hexane, which is purified by silica gel chromatography.

EXAMPLE 6 several times ether. The combined ether layers are washed several times with brine and dried over mag- EXAMPLE 7 7 To a suspension of l g. of sodium hydride in 20 of tetrahydrofuran is added a solution of 10 g. of 2- 'hydroxy-4-mesyloxy-3,3,6,6 tetra-methylbicyclo [3.2.0rr hexane. The solution is stirred for 2 hrs at 25 and poured into brine. After the addition of 200 ml. of ether, the organic phase is washed twice with brine, dried over magnesium sulfate, and evaporated in vacuo to yield 2,2-dimethyl-3-(2'-methyl-l'-propeny1)- cyclopropane- 1 -carboxaldehyde.

EXAMPLE 8 Toa solution of l g. of propenyl)-cyclopropane-l-carboxaldehyde in 20 ml. of methanol are added 1.7 g. of sodium cyanide, 0.6 g. of

acetic acid, and 12g. or manganese dioxide. The mixture is stirred for 12 hours at25 and filtered. The filtrate is evaporated to near dryness, suspended in 20 ml. of water, and extracted several times with ether. The extracts are washed with 5 percent sodium bicarbonate and brine, and dried over magnesium sulftate. Evaporation of the dried extracts yields a mixtu're of c'is and trans methyl chrysanthemates, which can be' separated by fi as chro'rnatography Isomeriza'tion of the mixture to e equilibrium mixture-predominantly trans-can be achieved either thermally or with base.

E LE9 A. The diketone of formula X (3.5 g.) is dissolved in 15 ml. of glacial acetic acid by warming to 50. Bromine (1.15 ml.) is added dropwise and then after cooling to room'temperature, the mixture is allowed to stand overnight. Water is added and then after about 2 hours, the mixture is filtered to yield the bromide of formula X] which can be purified by recrystallization from hexane.

B. A 57 percent sodium hydride oil dispersion (4.9 g.) is washed with hexane and suspended in ml. of: tetrahydrofuran. A solution of 28 g. of the bromide of. formula X1 in 60 ml. of tetrahydrofuran is added: slowly. The mixture is stirred for 0.5 hour and thenpoured into brine, diluted with ether and washed twice with saturated brine. The combined organic layers are dried, concentrated and the concentrate to yield 3,3,6,6-tetramethylbicyclo [3.1.0] hexane-2,45 dione (formula 1). I I

C. To a mixture of 5 g. of dirnedone, 19.9 g. of sium carbonate and 50 ml. of acetone is added a solution of 20.5 g. of methyliodide in 20 ml. of acetone and then the mixture is refluxed for 16 hours. Then after standing for 24 hours, the suspension is filtered, filtrate? evaporated under reduced pressure and the product; (the diketone of formula X) crystallized from'ether-i hexane.

EXAMPLE 10 A mixture of the diketone of formula X (1.9 g.) and pyridino hydrobromide perbromide (3.62 g.) and 50- ml. of glacial acetic acid is stirred for 0.5 hour and then refluxed for about 10 minutes. The mixture is cooled, diluted with water and allowed to stand. The crystalline: product of formula Xl is recovered by filtration'and recrystallized from hexane.

What is claimed is: I

1. A compound of formula: 7 i

wherein R is methyl or tolyl.

2. A compound according to claim 1 wherein R is methyl.

5 tolyl.

1 wherein R is 

2. A compound according to claim 1 wherein R is methyl.
 3. A compound according to claim 1 wherein R is tolyl. 